Optical molecular tomography based on fluorescence and bioluminescence has emerged as a major area of biomedical imaging. It is instrumental for localizing and quantifying molecular and cellular features in small animal models of human diseases, and helps monitor pathological changes, evaluate therapeutic responses, and facilitate drug research and development. Optical molecular imaging captures diffusive photons through the biological tissue. The photon transport in such media is mainly characterized by absorption and scattering. The radiative transport equation is theoretically accurate but computationally impractical. The most popular model for biomedical optics is the diffusion approximation that approximately describes the interaction of photons with the biological tissue but it only works well under certain conditions such as in highly scattering and weakly absorbing media. This limitation significantly compromises multi- spectral optical molecular imaging due to the mismatch between the diffusion approximation and the physical reality. For example, bioluminescence imaging involves a spectral range [400nm, 600nm] over which there is relatively large absorption in solid mouse organs, rendering the diffusion approximation quite inaccurate. Moreover, the diffusion approximation is problematic in the high frequency mode as used in fluorescence molecular imaging. The model mismatch would have the most adverse effect on image quality in solving ill-posed optical tomography problems. Currently, there is no photon propagation model that is well-rounded for optical molecular imaging. Our overall goal of this project is to develop a phase approximation model to replace the diffusion approximation model for optical molecular imaging. The new model is based on a generalized phase function, make the diffusion approximation a special case, mathematically equivalent to the radiative transport equation and computationally comparable to the diffusion approximation model. Our preliminary data show that our phase approximation works as accurately as the radiative transport equation over a broad range of biologically relevant optical parameters. The specific aims are to (1) formulate the phase approximation model systematically with respect to the photon fluence rate and flux vector in the steady-state, frequency and time-resolved modes respectively, (2) develop practical algorithms based on the phase approximation to describe the photon transport in the mouse anatomy, (3) perform numerical simulation and phantom experiments to evaluate and validate the phase approximation based algorithms with strong absorbers, near light sources, across boundaries, and in the high frequency mode. Upon completion of this project, the relative errors of the photon fluence rate and flux vector obtained from the phase approximation model will have been validated as <5% as compared with the Monte Carlo data and experimental data over any set of biologically relevant optical parameters, and >30% accuracy improvement been made against the diffusion approximation model for albedo <10. The computational cost of the phase approximation model will have been evaluated as <20% increment than that of the diffusion approximation model. The proposed techniques will significantly enhance optical molecular imaging for a wide variety of pre-clinical imaging applications. In this project, we will develop a novel photon transport model - the phase approximation model to replace the diffusion approximation model that has been popular in the bio-photonics field for decades and exclusively used for optical molecular tomography. Over a broad range of biologically relevant optical parameters, the new model will produce results consistently more accurate than the diffusion approximation model at a computational cost comparable to the diffusion approximation counterpart. The proposed techniques will significantly improve optical biomedical imaging for a wide variety of pre-clinical applications.